Practice Essentials

Pediatric chronic autoimmune neutropenia (pediatric chronic AIN, also called chronic benign neutropenia or chronic idiopathic neutropenia) is a benign, self-limiting condition affecting infants and toddlers.
[1] The name usually refers to primary, not secondary, AIN.

Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1000/μL in infants and less than 1500/μL in older children.

Despite the fact that the condition is called autoimmune neutropenia, antibodies against neutrophils may not be demonstrated in a significant number of cases. When antibodies do occur, their presence has no prognostic or therapeutic implications, since equal proportions of antibody-positive and antibody-negative cases recover spontaneously. In addition, antibodies were demonstrated in patients who were proven to have severe congenital neutropenia due to a mutation of the ELANE gene.
[2]

ANC alone does not allow differentiation of AIN from severe congenital neutropenia, since in both disorders the ANC may be extremely low. Indeed, differentiation from severe congenital neutropenia and benign ethnic neutropenia may be difficult. When severe congenital neutropenia is suspected, a molecular diagnostic test is indicated.

Secondary AIN occurs in a setting of systemic autoimmune disease, infection, neoplasia, bone marrow or organ transplantation, drug administration, or immunodeficiency. Secondary AIN develops in much older children than does primary AIN, is more common in girls, and is clinically more prone to serious infections; spontaneous recovery is rare.
[3]

Chronicity means that neutropenia persists longer than 3 months. Primary AIN in infants and children lasts, on average, 20 months. Although the clinical course of AIN is usually benign, a minority of children experience frequent infections.

AIN has an excellent prognosis. In severe cases of the disease, treatment usually consists of regular administration of granulocyte colony-stimulating factor (G-CSF) (filgrastim).

Determine the severity of neutropenia and the severity of concurrent infection

Progressive neutropenia over a course of days requires rapid workup, including hematology consultation

History of parent consanguinity, family history of neutropenia, or past or current life-threatening infection suggests severe congenital neutropenia rather than AIN and requires genetic workup

When the history and serial laboratory studies are consistent with AIN, a test to detect neutrophil antibodies (human neutrophil antigens [HNA]-1, 2, and 4) is not needed

Be aware that there are multiple systemic diseases whose features include neutropenia, such as Hermansky-Pudlak syndrome, Barth syndrome, and Shwachman-Diamond syndrome; look for nonhematologic abnormalities and incorporate them into the differential diagnosis

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Background

The definition of neutropenia in infants is different from that in adults. In infants aged 2 weeks to 1 year, the lower limit of the normal neutrophil count is 1000/µL. After the first year of life, the lower limit is 1500/µL, as in adults.

The most common form of neutropenia in infants and young children is transient neutropenia occurring with or following a viral illness. It resolves itself within 2 weeks. If it lasts longer than that, or if the child is very ill, then a full workup for neutropenia is in order.

The most common type of chronic neutropenia (neutropenia lasting for 3 months or longer) in pediatric patients is chronic benign neutropenia of childhood. Chronic benign neutropenia can be regarded as a synonym for primary AIN in children.
[4] Some investigators have also used the term chronic idiopathic neutropenia as a synonym for chronic benign neutropenia when the presence of antibodies cannot be demonstrated.
[1]

The mean age at diagnosis of AIN is 6-12 months, with a range of 3-30 months. Spontaneous recovery occurs by age 5 years, and the mean duration of neutropenia is approximately 20 months.

Primary and secondary autoimmune neutropenia

AIN is either primary or secondary. In primary AIN, neutropenia is the only abnormality. Infections associated with the primary form are usually limited and mild.
[5] Primary neutropenia occurs in infants and toddlers, and spontaneous recovery is the rule.

Older children, adolescents, and young adults predominantly develop secondary AIN. In this condition, other primary pathologies occur, including systemic autoimmune disease, infections, malignancy, or immunodeficiency. It can also be associated with drug administration and bone marrow or organ transplantation. AIN that occurs in the older pediatric age group and adolescents must be regarded as a totally distinct entity from chronic benign neutropenia. The clinical course of secondary AIN is not benign. It is more common in females and is associated with severe infections, with spontaneous recovery being very rare. Lymphopenia, direct antiglobulin test (DAT)–positive hemolytic anemia, and/or thrombocytopenia are common in secondary AIN, developing later or at the same time.
[3] Antiphospholipid antibody syndrome is common, and ultimately, systemic lupus, Felty syndrome, Sjögren syndrome, autoimmune thyroiditis, celiac disease, and/or a lupuslike illness predominate. Therefore, in this age group, a rigorous search for evidence of other autoimmune phenomena should be made.

A case of secondary autoimmune neutropenia. This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.

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Etiology

Lalezari and colleagues demonstrated neutrophil antibodies in 119 of 121 infants and children with chronic neutropenia, thereby establishing the autoimmune nature of the disease.
[6] In the study, all patients had at one time an absolute neutrophil count of less than 500/µL (see the Absolute Neutrophil Count calculator).

AIN is similar to immune thrombocytopenic purpura (ITP) of young children, a more common cytopenia in children. ITP is believed to be triggered by a viral infection and, in some individuals, by immunization. Whether autoimmune neutropenia is commonly triggered by similar etiologies is not known. A similar age group is affected, and recovery is expected in both. Some studies have shown an association with parvovirus B19 infection. Recently, Nakamura et al showed deficiencies in regulatory T cell (CD4+, CD25+) in children with autoimmune neutropenia.
[7] Thus, it may be a phenomenon of physiologically delayed maturation of immune regulation.

When identified in AIN, antibodies most commonly include immunoglobulin G (IgG) antibodies against neutrophil glycosylated isoforms of FC gamma RIIIb (or CD 16b) and human neutrophil antigen 1 (HNA1) and, less commonly, against HNA4, which are linked to the plasma membrane via a glycosylphosphatidylinositol anchor.

The human neutrophil antigen (HNA) system consists of HNA-1 through HNA-5. Of these, most common antibodies are directed against HNA-1, which consists of NA-1, NA-2, and SH. They are not anti–human leukocyte antigen (HLA) antibodies. Anti-HLA antibodies may be present, but it is very rarely the cause of AIN.

Bruin et al demonstrated that in patients with AIN, antibodies were exclusively directed against the NA alloantigens, whereas in patients with secondary autoimmune neutropenia, antibodies had pan-FC gamma RIIIb specificity.
[8] though other researchers have shown that at the outset of AIN, antibodies against FCγRIIIb may be present (see below).

Bone marrow examination findings are variable and not diagnostic. Bone marrow may be normal, show late-stage maturation arrest, be hyperplastic, or be hypoplastic. In rare cases, granulocyte phagocytosis has been reported.
[9]

In a study by Perdikogianni et al, circulating granulocyte colony-stimulating factor (G-CSF) levels (serum or plasma) were found to be normal, even during the neutropenic period, except when patients had infections.
[10] On the other hand, Kobayashi et al found that the patient’s sera contained mildly but significantly elevated concentration of G-CSF compared with the control sera.
[11]

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Epidemiology

The incidence of autoimmune neutropenia does not vary among different ethnic populations.

A Scottish study estimated that in the Scottish population, the incidence of autoimmune neutropenia is 1 in 100,000 children per year.
[12] This may have been an underestimate, however, because laboratory tests are not usually performed in most cases of autoimmune neutropenia.

Autoimmune neutropenia has a slight preponderance in girls in one study,
[6] but not in others.
[13] The mean age at diagnosis of autoimmune neutropenia is 6-12 months, with a range of 3-30 months.

A high frequency of benign neutropenia is widely recognized in African Americans, Yemenite and Falasha Jews, Black Beduin, blacks of South African extraction, Ethiopians, West Indians, Arab Jordanians, and various tribal groups inhabiting the United Arab Emirates.
[14] A study showed the median ANC of children with benign ethnic neutropenia to be 893 x 106/L.
[15] The gene responsible for this form of neutropenia is identified as the DARC (Duffy antigen/receptor chemokine) gene, although the exact mechanism that causes neutropenia is still to be elucidated.
[16, 17] In the age group (6 months to 3 years) when AIN is common, it may be impossible to distinguish these two entities in a given child.

Morbidity

Infections associated with primary AIN, which are usually limited and mild, include just fever, otitis media, upper respiratory tract infection, common colds, viral gastroenteritis, skin infection, stomatitis, and gingivitis. Sepsis and pneumonia are rare. Hajishengallis et al reported on the development of AIN-related periodontal disease in a child aged 2 years.
[18] In a study done at St Jude Children’s Research Hospital on children with all types of chronic neutropenia, otolaryngological infections predominated, consisting of recurrent otitis media (81%), viral upper respiratory tract infection (67%), oral ulcers or gingivitis (53%), tonsillitis (39%), and sinusitis (37%).
[19]

A case of secondary autoimmune neutropenia. This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.

This is in contrast to the severe, life-threatening infections (quite often systemic) experienced by infants with severe congenital neutropenia (Kostmann disease and other types), children with aplastic anemia, older children with secondary AIN, and children with neutropenia who are receiving chemotherapy. An Italian study showed that 40% of children with secondary AIN had severe infections, as compared with 12% of children with primary AIN.
[3]

In another study, of 73 children with neutropenia, Fioredda et al reported a rate of 0.66 infections per patient with AIN, compared with 5.75 infections per patient with severe congenital neutropenia.
[20] (The AIN figure may be an overestimate, however, since there may have been a selection bias; the neutropenia registry used in the study contained more severely affected AIN patients.) The reasons for this difference between primary autoimmune and severe congenital neutropenia may be related to the fact that individuals with AIN have an adequate bone marrow neutrophil reserve and can therefore mount some level of neutrophil response to an infection, even though these neutrophils are rapidly destroyed; this is in contrast to patients with poor or no bone marrow reserve.

Although febrile illnesses appear to be more common in children with AIN than in healthy children, AIN usually does not affect the child's growth and development, although some exceptions occur. (See History.)

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Prognosis

The prognosis in primary chronic neutropenia is excellent. The condition usually lasts only 2-3 years before spontaneous resolution, and virtually all patients recover by age 5 years.

Spontaneous recovery after 6-24 months is typical. If it persists beyond age 4-5 years, consider other diagnoses (secondary neutropenia). It is important to follow these patients into recovery for this reason.

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Patient Education

Thoroughly discussing the natural history with the patient’s parents and/or caregivers is important, since this can prevent undue anxiety created by low neutrophil counts.

In addition, because medical advice is usually sought after infections have occurred in a child with autoimmune neutropenia, discussing the condition’s natural history validates the experience of the parents and/or caregivers and, in turn, increases their confidence in the physician's diagnosis and treatment.

It is important for patients to maintain good dental hygiene in order to prevent gingivitis, stomatitis, and other mucous membrane infections of the mouth.

A case of secondary autoimmune neutropenia. This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.

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Contributor Information and Disclosures

Author

Susumu Inoue, MD Professor of Pediatrics and Human Development, Michigan State University College of Human Medicine; Clinical Professor of Pediatrics, Wayne State University School of Medicine; Director of Pediatric Hematology/Oncology, Associate Director of Pediatric Education, Department of Pediatrics, Hurley Medical Center